Renovascular hypertension is a major cause of morbidity and mortality in the United States. Optimal management of patients with renal artery stenosis (RAS) is a subject of considerable controversy, in large part because basic signaling mechanisms underlying the development of cardiovascular and renal disease in the setting of RAS are not well understood. Unilateral RAS has been employed as a model of human renovascular hypertension. This lesion induces vascular hypertrophy and sclerosis, interstitial fibrosis, tubular atrophy, and interstitial inflammation in the stenotic kidney and compensatory hypertrophy in the contralateral kidney. The central hypothesis of this Program Project application is that the morphologic alterations in the stenotic and contralateral kidneys following unilateral RAS are triggered by hemodynamic alterations, tissue hypoxia in the stenotic kidney, oxidative. stress, and activation of the renin-angiotensin system. These "initiating factors" are the primary focus of Projects 1, 2, and 4. The overall hypothesis to be tested in Project 3 is that these "initiating factors" are responsible for induction of TGF-p, the cell cycle inhibitors p21 and p27, and the MAPK pathways, which are differentially regulated in the stenotic and contralateral kidney. In Specific Aim 1, we will test the hypothesis that TGF-p, p21/p27, and p-ERK are persistently elevated in the stenotic kidney, leading to interstitial fibrosis and tubular atrophy, and are transiently elevated in the contralateral kidney, leading to compensatory hypertrophy/hyperplasia. In Specific Aim 2, TGF-pl signaling will be interrupted through the use of TGF-p1 neutralizing antibodies and mice bearing homozygous deletion of the SmadS gene, an essential intermediate in TGF-pl signaling, to test the hypothesis that TGF-p plays a central role in the development of renal atrophy in the stenotic kidney and compensatory hypertrophy/hyperplasia in the contralateral kidney. In Specific Aim 3, we will employ p21 and p27 knockout mice to test the hypothesis that deletion of p21 and/or p27 will limit the extent of interstitial fibrosis in the stenotic kidney and will promote a hyperplastic rather than hypertrophic response in the contralateral kidney. Finally, we will test the hypothesis that inhibition of ERK or other MAPK pathways will limit the development of interstitial fibrosis in the stenotic kidney and compensatory hypertrophy and/or hyperplasia in the contralateral kidney. The proposed studies will define critical elements of signaling pathways triggered by RAS and may provide the mechanistic basis for interventions directed towards arresting the development of irreversible renal injury in patients with renovascular hypertension.